Chemical compounds

Abstract

The present invention provides compounds of formula (I) wherein R<SUP>1 </SUP>and R<SUP>2 </SUP>are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.

What is claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein:
 R 1  is C 1 -C 6  alkyl; and 
 R 2  is C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, 
 wherein said C 1 -C 6  alkyl is optionally substituted by CF 3 . 
 
     
     
       2. A compound according to  claim 1  wherein R 1  is C 1 -C 4  alkyl. 
     
     
       3. A compound according to  claim 1  wherein R 1  is methyl. 
     
     
       4. A compound according to  claim 1  wherein R 2  is C 1 -C 4 alkyl optionally substituted by CF 3 . 
     
     
       5. A compound according to  claim 1  wherein R 2  is methyl, ethyl or i-propyl. 
     
     
       6. A compound according to  claim 1  wherein R 2  is cyclopropyl or cyclobutyl. 
     
     
       7. A compound selected from:
 N-{(1S)-3-[3-endo-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(5-Cyclobutanecarbonyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(5-Cyclopropanecarbonyl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(5-Isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(2-Methyl-5-propionyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(5-Butyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(2-Methyl-5-(2,2-dimethyl-propionyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 N-{(1S)-3-[3-endo-(2-Methyl-5-(3,3,3-trifluoro-propionyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3-fluorophenyl)propyl}acetamide; 
 
       and pharmaceutically acceptable salts thereof. 
     
     
       8. A pharmaceutical composition comprising a compound according to  claim 1  or  7 , together with one or more pharmaceutically acceptable excipients, diluents or carriers. 
     
     
       9. A pharmaceutical composition according to  claim 1  or  7 , together with one or more pharmaceutically acceptable excipients, diluents or carriers, and further comprising one or more additional therapeutic agents. 
     
     
       10. A process for preparing a compound according to  claim 1  or  7 , comprising:
 (A) reacting a compound of formula (II) 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (III) 
       
         
           
           
               
               
           
         
         (B) reacting a compound of formula (XVI) 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (V) 
       
         
           
           
               
               
           
         
         (C) reductively aminating an aldehyde of formula (XIX) 
       
       
         
           
           
               
               
           
         
       
       with an amine of formula (XX) 
       
         
           
           
               
               
           
         
         (D) reductively aminating a nitrile of formula (XXI) 
       
       
         
           
           
               
               
           
         
       
       with an amine of formula (XX);
 (E) alkylating an amine of formula (XX) or a salt thereof with a compound of formula (XXII) 
 
       
         
           
           
               
               
           
         
         (F) reducing an enamide of formula (XXIII) 
       
       
         
           
           
               
               
           
         
         (G) reacting the amine of formula (II), or a metal salt thereof, with an ester of formula (XXIV)
   R 1 CO 2 EsGp  (XXIV)
 
 
         wherein:
 R 1  is C 1 -C 6  alkyl; and 
 R 2  is C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, 
 wherein said C 1 -C 6  alkyl is optionally substituted by CF 3 ; and 
 
       
       wherein Lg is a leaving group, and EsGp is an ester-forming group. 
     
     
       11. A compound of formula (II), (IV), (VI), (VII), (XVI), (XVII),(XVIII), (XX) or (XXIII): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein:
 Pg is an amino protecting group; 
 R 1  is C 1 -C 6  alkyl; and 
 R 2  is C 1 -C 6  alkyl or C 3 -C 7  cycloalkyl, 
 wherein said C 1 -C 6  alkyl is optionally substituted by CF 3 .